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Title: Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity

Abstract

Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protectedmore » against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.« less

Authors:
 [1];  [2];  [3];  [4];  [2];  [1];  [5]
  1. Liver Research Institute, University of Arizona, Tucson, AZ 85724 (United States)
  2. Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, NCI at NIEHS, Research Triangle Park, NC 27709 (United States)
  3. Department of Pathology, Brackenridge Hospital, Austin, TX 78701 (United States)
  4. Institute of Molecular Biology and Biochemistry, Medical University Graz, Center for Molecular Medicine, 8010 Graz (Austria)
  5. Liver Research Institute, University of Arizona, Tucson, AZ 85724 (United States). E-mail: jaeschke@email.arizona.edu
Publication Date:
OSTI Identifier:
20850431
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 216; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2006.04.010; PII: S0041-008X(06)00150-5; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALANINES; ANTIBODIES; BIOLOGICAL STRESS; CHLORIDES; GENES; HEME; INFLAMMATION; INJURIES; LIVER; LYMPHOKINES; MACROPHAGES; MICE; NECROSIS; NEUTROPHILS; OXIDASES; OXIDIZERS

Citation Formats

Cover, Cathleen, Liu Jie, Farhood, Anwar, Malle, Ernst, Waalkes, Michael P., Bajt, Mary Lynn, and Jaeschke, Hartmut. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. United States: N. p., 2006. Web. doi:10.1016/j.taap.2006.04.010.
Cover, Cathleen, Liu Jie, Farhood, Anwar, Malle, Ernst, Waalkes, Michael P., Bajt, Mary Lynn, & Jaeschke, Hartmut. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. United States. doi:10.1016/j.taap.2006.04.010.
Cover, Cathleen, Liu Jie, Farhood, Anwar, Malle, Ernst, Waalkes, Michael P., Bajt, Mary Lynn, and Jaeschke, Hartmut. Sun . "Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity". United States. doi:10.1016/j.taap.2006.04.010.
@article{osti_20850431,
title = {Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity},
author = {Cover, Cathleen and Liu Jie and Farhood, Anwar and Malle, Ernst and Waalkes, Michael P. and Bajt, Mary Lynn and Jaeschke, Hartmut},
abstractNote = {Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2) was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.},
doi = {10.1016/j.taap.2006.04.010},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 216,
place = {United States},
year = {Sun Oct 01 00:00:00 EDT 2006},
month = {Sun Oct 01 00:00:00 EDT 2006}
}